The majority of people wearing non-gas permeable hard (PMMA; polymethylmethacrylate) lenses, and a significant percentage of soft contact lens wearers experience mild to moderate corneal edema during lens wear. In "extended wear" lens users, the incidence and severity of corneal edema is greater, particularly during sleep. Other corneal complications resulting from the extended lens wear are corneal inflammation, ulcerative keratitis, infection, neovascularization, epithelial microcysts and endothelial polymegathism.
Contact lens wear causes corneal epithelial hypoxia, which results in stimulation of anaerobic glycolysis and increased production and accumulation of osmotically active lactate in the stroma. The lactate diffuses to the stroma, where it creates an osmotic imbalance leading to increased corneal hydration (swelling). The lens wear also produces an increase in CO.sub.2 tension brought on by limited CO.sub.2 lens transmissibility. This increase in CO.sub.2 at the tear-film/lens interface, combined with accumulation of stromal lactate, contributes to a reduction in corneal pH (corneal acidosis). When the eye lids are closed, the CO.sub.2 tension will increase further and the epithelial oxygen availability is reduced. These effects lead to a sustained decrease in epithelial pH while a lens is being worn and the acidification will be at its greatest when the eyes are closed. This acidification could easily lead to many corneal changes, which are responsible in part for the above-indicated corneal complications.
One solution to preventing the hypoxia would be the use of contact lens material of higher oxygen permeability (e.g., a siloxane or silicon copolymer). Unfortunately, even lenses of the highest oxygen permeabilities are known to cause significant corneal edema.
Osmotic therapy using hypertonic NaCl is being practiced, but it also affects the normal cornea. Lactate dehydrogenase (LDH) inhibitors, sodium oxalate and sodium oxamate, have been reported to inhibit the progress of experimental edema by reducing the accumulation of stromal lactate without having any effect on corneal thickness in nonedematous cornea in vitro (M. D. Rohde et al., Current Eye Research, 1986, 5, 751-758). See also M. E. Clark, J. A. M. Hinke and M. E. Todd, J. Exp. Biol. (1981), 90, 43-63, which is incorporated in its entirety by reference.
U.S. Pat. No. 5,102,670 to Abraham, incorporated herein by reference, discloses a method for treating or preventing ocular swelling and corneal-conjunctival inflammation. The method involves administration to the eye of an amount of a heme oxygenase inducing agent such as SnCl.sub.2. See also Nahas, G. G., Pharmacol. Rev., 14 (1962), 447, which is incorporated herein in its entirety by reference. An increase of heme oxygenase leads to a decrease in 12(R)-hydroxy-eicosatetraenoic acid [12(R)-HETE] and 12-hydroxy-5,8,14-eicosatrienoic acid [12(R)-DIHETE] in the arachidonic acid cascade. 12(R)-HETE is known to inhibit corneal endothelial ATPase (adenosine triphosphatase) which is an enzyme responsible for maintaining proper corneal water content and thus thickness. 12(R)-DIHETE is a chemical mediator responsible for vasodilation of conjunctival blood vessels and inflammation. Therefore, an increased level of heme oxygenase eventually leads to diminished corneal swelling and inflammation in the conjunctiva and cornea.
However, Geroski et al. Invest. Ophthal. Vis. Sci., Vol. 34, no. 4, 1404, 1993, have recently shown that 12(R)-Hete can inhibit corneal endothelial ATPase by at most 29%. This fact, together with the known osmotic effects of high corneal stromal lactate to increase corneal swelling through a purely physical-chemical mechanism, and the observations of Conners et al., Invest. Ophthal. Vis. Sci., Vol 33, No. 4, 780, 1992, that heme oxygenase induction reduced contact lens induced corneal swelling by only 26%, indicates that while some progress is being made to prevent hypoxia-associated corneal complications, there is a definite need for an improved method or ophthalmic composition to prevent or treat hypoxia complictions. With the advent of extended wear contact lenses, it becomes increasingly important to avoid such problems.